Journal
GENES & DEVELOPMENT
Volume 24, Issue 24, Pages 2760-2765Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.1998010
Keywords
Bcl-6; NF-kB; macrophage; inflammation; cistrome; ChIP-seq
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Funding
- NIH [1K08HL092298, P01HL088093, U19DK062434, R37DK057978, R01HD027183, R01HL086566, P30DK063491/DERC]
- Dr. Alan Fogelman and the David Geffen School of Medicine at University of California at Los Angeles
- Samuel Waxman Cancer Research Foundation
- Chapman Foundation
- Howard Hughes Medical Institute
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In the macrophage, toll-like receptors (TLRs) are key sensors that trigger signaling cascades to activate inflammatory programs via the NF-kappa B gene network. However, the genomic network targeted by TLR/NF-kappa B activation and the molecular basis by which it is restrained to terminate activation and re-establish quiescence is poorly understood. Here, using chromatin immunoprecipitation sequencing (ChIP-seq), we define the NF-kappa B cistrome, which is comprised of 31,070 cis-acting binding sites responsive to lipopolysaccharide (LPS)-induced signaling. In addition, we demonstrate that the transcriptional repressor B-cell lymphoma 6 (Bcl-6) regulates nearly a third of the Tlr4-regulated transcriptome, and that 90% of the Bcl-6 cistrome is collapsed following Tlr4 activation. Bcl6-deficient macrophages are acutely hypersensitive to LPS and, using comparative ChIP-seq analyses, we found that the Bcl-6 and NF-kappa B cistromes intersect, within nucleosomal distance, at nearly half of Bcl-6-binding sites in stimulated macrophages to promote opposing epigenetic modifications of the local chromatin. These results reveal a genomic strategy for controlling the innate immune response in which repressive and inductive cistromes establish a dynamic balance between macrophage quiescence and activation via epigenetically marked cis-regulatory elements.
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